PI3K has been shown to play an important role in mitogenic signaling by protein-tyrosine kinases. Studies by the Applicant established that transformation of hematopoietic cells by p210 BCR/abl, a tyrosine kinase fusion protein responsible for CML, is accompanied by PI3K activation. The central hypothesis of the proposal is that activation of PI3K plays a key role in p210 BCR/abl signaling and blocking of PI3K may revert BCR/abl induced transformation. Studies by the Applicant have shown that the product of protooncogene, cbl, is phosphorylated in CML cells, is a direct substrate for abl kinase, and recruits the Ras and PI3K pathways. The Applicant will determine the role of cbl in the activation of the p21ras and PI3K pathways. Various mutants of cbl and PI3K will be constructed and selective dominant-negative mutants which block BCR/abl induced mitogenesis will be analyzed in a CML-scid model.